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Stopping epilepsy treatment in seizure remission: Good or bad or both?

Open ArchivePublished:September 09, 2016DOI:https://doi.org/10.1016/j.seizure.2016.09.003

      Highlights

      • Discontinuation of drug treatment in remission does not seem to affect the long-term prognosis of epilepsy.
      • However, there is a two-fold risk of seizures for the first 2 years after stopping AEDs.
      • Twenty percent of patients do not become seizure-free immediately after restarting AED after relapse.
      • The list of potential pitfalls of stopping AEDs is long.
      • Patients with juvenile myoclonic epilepsy, those with prior withdrawal attempts and late remission should not be encouraged to stop AEDs.
      • We need new anti-seizure drugs with antiepileptogenic effects to prevent seizure relapse after withdrawal.

      Abstract

      Purpose

      To review the outcome of epilepsy after stopping antiepileptic drugs in remission.

      Results

      Stopping antiepileptic drugs (AEDs) in remission is routinely done in many patients. Although the consequences of an unexpected relapse seizure in the 2 years after stopping AEDs may cause anguish and social issues, the impact on the long term seizure outlook of the epilepsy is minimal, if any. Discontinuation of drug treatment does not seem to affect the long-term prognosis but exposes patients who were seizure-free for years to a transient two-fold risk of seizures for the first 2 years after stopping AEDs. In addition, 20% of patients who were seizure-free for years, do not become seizure-free immediately after restarting AED treatment after relapse. The list of potential pitfalls is long. Patients with juvenile myoclonic epilepsy, those with prior withdrawal attempts and late remission have a higher risk of relapse.

      Conclusion

      Stopping AEDs in remission does not affect the long-term patterns of epilepsy and some patients report a better general health in a life without AEDs. High-risk patients should not be generally encouraged to stop their AEDs in remission. We need new drugs that combine anti-seizure and antiepileptogenic effects to prevent seizure relapse and flare up of epilepsy after stopping AEDs in remission.

      Keywords

      1. Introduction

      The ideal objective of treating a person with epilepsy is of course to induce remission by usage of antiepileptic drugs (AEDs) and ultimately stop the AEDs without causing seizure recurrence [
      • Schmidt D.
      • Schachter S.C.
      Drug treatment of epilepsy in adults.
      ]. Nearly 70% of patients with new-onset epilepsy eventually enter prolonged terminal seizure remission during treatment with AEDs [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ,
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy.
      ]. The continued use of AEDs in children and adults may be associated with adverse effects in a substantial fraction of the exposed population, including behavioral and cognitive and other chronic side effects [
      • Schmidt D.
      • Schachter S.C.
      Drug treatment of epilepsy in adults.
      ]. Further disadvantages of continuing treatment indefinitely include a higher risk of teratogenicity, drug interaction with concurrent medications, and, last not least, the concern that treatment may be unnecessary. Understandably, many patients wish to lead a life without taking drugs and plan to stop their AEDs drugs after being seizure free for a while [
      • Schmidt D.
      • Schachter S.C.
      Drug treatment of epilepsy in adults.
      ]. As a consequence, AEDs are routinely withdrawn in the majority of patients entering prolonged seizure remission during drug treatment [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy.
      ,
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      ]. Surprisingly, class I evidence on the consequences of stopping versus continuing treatment on seizure outcome and general health are rather limited and the list of potential pitfalls when attempting to stop AEDs is long [
      • Schmidt D.
      • Schachter S.C.
      Drug treatment of epilepsy in adults.
      ]. The decision to continue or to stop AED treatment in patients with prolonged seizure remission is a difficult one and requires a full assessment of the risk-benefit balance of drug discontinuation for the individual patient. In this brief overview, we discuss the best available evidence on outcome after stopping treatment of epilepsy in remission during drug treatment and how to avoid common pitfalls with an emphasis on more recent data. For a review of the earlier literature including stopping AEDs after surgical remission see [
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      ]. We will not be able to discuss stopping AEDs following surgical remission or in cases of a misdiagnosis of epilepsy.

      2. Seizure outcome in patient populations after stopping AEDs in remission

      The short-term recurrence risk after stopping AEDs in seizure free patient populations is well established. Three major lines of evidence exist. However, there is only one small randomized double-blind trial for AED withdrawal of selected adults becoming seizure-free on AEDs [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study).
      ]. The best evidence from the earlier literature comes from a large unblinded randomized trial in patients who became seizure-free on AED treatment [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Randomized study of antiepileptic drug withdrawal in patients in remission.
      ], and several non-randomized observational studies [
      • Overweg J.
      • Binnie C.D.
      • Oosting J.
      • Rowan A.J.
      Clinical and EEG prediction of seizure recurrence following antiepileptic drug withdrawal.
      ,
      • Callaghan N.
      • Garrett A.
      • Goggin T.
      Withdrawal of anticonvulsant drugs in patients free of seizures for two years. A prospective study.
      ,
      • Matricardi A.
      • Bertamino F.
      • Risso D.
      Discontinuation of anti-epileptic therapy: a retrospective study of 86 children and adolescents.
      ,
      • Specchio L.M.
      • Tramacere L.
      • La Neve A.
      • Beghi E.
      Discontinuing antiepileptic drugs in patients who are seizure free on monotherapy.
      ]. Finally, a number of reviews offer valuable information [
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      ,
      • Schmidt D.
      • Löscher W.
      Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience.
      ,
      • Sirven J.I.
      • Sperling M.
      • Wingerchuk D.M.
      Early versus late antiepileptic drug withdrawal for people with epilepsy in remission.
      ].

      2.1 The Akershus double-blind randomized study

      The Akershus study is the first double-blind, randomized trial of AED withdrawal in remission [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study).
      ]. In this study, 15% of patients randomized to treatment withdrawal and 7% of those randomized to remain on treatment had a recurrence at 12 months, a non-significant difference. However, those who stopped AEDs improved significantly in their neuropsychological performance. In this benchmark study, Lossius and colleagues [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study).
      ] randomized carefully chosen adult patients, who were seizure-free for more than 2 years on AED monotherapy, to AED withdrawal (n = 79) or no withdrawal (n = 81), and followed them up for 12 months, or until seizure recurrence. After withdrawal, recurrence rates were 27% after a median of 41 months off medication. Adverse effects including behavioral and cognitive side effects have been shown to improve after drug withdrawal [
      • Lossius M.I.
      • Hessen E.
      • Mowinckel P.
      • Stavem K.
      • Erikssen J.
      • Gulbrandsen P.
      • et al.
      Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study).
      ]. Withdrawal did however not affect general health measured as quality of life and the EEG findings. Predictors for remaining seizure-free after AED withdrawal over 1 year were normal neurological examination at presentation and, in the view of the authors, use of carbamazepine prior to withdrawal.
      Although the Akershus study is first in class, and the authors are to be commended for this, it needs to be considered in the light of several limitations as any study however good it may be. One weakness is the limited generalizability of the findings as the study excluded patients with a high risk of seizure relapse after withdrawal, for example, patients with idiopathic generalized epilepsy showing epileptiform discharges and those with juvenile myoclonic epilepsy, patients seizure-free on polytherapy, and those with a history of two prior withdrawal attempts were not eligible. The restricted access unfortunately introduced a substantial bias toward lowering the risk of seizure relapses, obviously in both arms. Another limitation is that patients were not randomized on prior AED use, thus the better outcome of withdrawal observed in those withdrawn from carbamazepine, may, in part, reflect a selection bias when treatment was started, and at least in our view, should not be taken as evidence that withdrawing patients from carbamazepine is more successful than withdrawal from other AEDs. Finally, the AED treatment, if any, and prognosis of seizures occurring after a relapse, if any, have not been included in the results. It would have been informative to learn if most patients had one seizure and remained seizure free after relapse or how often treatment was restarted and how successful it was in terms of regaining remission. This information would have been valuable for patient counseling.
      What are the implications of this important study? Foremost. AED withdrawal in adults is associated with a considerable risk of seizure-recurrence in one of six low-risk patients, more than double the risk in those who remain on drug. (Though the difference was not significant, possibly due to the limited power of the small number of patients in the trial.) Although some patients had improved neuropsychological outcome, general health, measured as quality of life was not better after withdrawal. This important finding is in general agreement with the benchmark MRC AED withdrawal study [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Randomized study of antiepileptic drug withdrawal in patients in remission.
      ] (see below), although Jacoby et al. [
      • Jacoby A.
      • Johnson A.
      • Chadwick D.
      Psychosocial outcomes of antiepileptic drug discontinuation. The Medical Research Council Antiepileptic Drug Withdrawal Study Group.
      ] found a benefit in a subgroup of patients of the MRC study who had a low risk of recurrence. Another important result of the Akerhus study was that remaining on AEDs did not fully protect from seizure recurrence. In fact, 2 years after withdrawal, there was no difference in recurrence rate between the withdrawal and the no withdrawal group. This shows that stopping AEDs in remission does not seem to influence the long-term seizure outcome of epilepsy. The Akershus study provided robust class I evidence about the benefits and risks of withdrawing AEDs in low-risk seizure-free adults that we did not have before. Patients and physicians are now better equipped to make the difficult decision to withdraw AEDs, after taking into account the individual risk profile of the patients regarding relapse and other important factors, such as the preference of the patient and consideration of the sometimes grave social consequences of a seizure relapse in patients who had been seizure free for years.

      2.2 MRC antiepileptic drug withdrawal study and subsequent reports

      The MRC study is an unsurpassed benchmark study because it is the first in class to uniquely assess the risk of seizures after stopping AEDs compared to continued treatment in a pragmatic trial conducted in 1013 patients who had been free of seizures for at least 2 years and were undecided whether to stop AEDs or not [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Randomized study of antiepileptic drug withdrawal in patients in remission.
      ]. The MRC AED withdrawal study provided unique evidence about the risk of seizures despite continued AED treatment. AED discontinuation doubles the risk of seizures for up to 2 years after stopping AED compared to continued treatment [
      • Chadwick D.
      • Taylor J.
      • Johnson T.
      Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group.
      ]. By 2 years after randomization, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free, but thereafter the differences between the two groups diminished. This suggests that the long-term seizure outcome is not affected by drug discontinuation. The main result of the MRC study was that AED discontinuation doubles the risk of seizures for up to 2 years after stopping AED compared to continued treatment [
      • Chadwick D.
      • Taylor J.
      • Johnson T.
      Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group.
      ]. Non-compliance with continued treatment apparently accounted for only a small proportion of the risk to the group continuing with treatment. The most important factors determining outcome were longer prior seizure-free periods (reducing the risk) and more than one antiepileptic drug and a history of tonic–clonic seizures (increasing the risk of relapse). Other factors (e.g., history of neonatal seizures, specific electroencephalographic features) seemed to have smaller effects, but even in such a large study the confidence intervals for these observations were wide [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Randomized study of antiepileptic drug withdrawal in patients in remission.
      ,
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Prognostic index for recurrence of seizures after remission of epilepsy.
      ]. The failure to predict the risk of recurrence for the individual patient even in this large study creates uncertainty and anguishes and is a matter of concern. The study group has since provided very useful information to delineate the individual risk which will be discussed below. Although both studies, the MRC study and the Akershus study, are most valuable, however both included subpopulations of patients by either excluding those with a high risk of relapse as in the Akerhus study or excluding those who unambiguously wished to stop their AEDs. Additional valuable information on the risk of relapse, albeit in a lower evidence class is available from selected reviews.

      2.3 Selected reviews

      The overall quite substantial risk of seizure relapse after treatment discontinuation has been well reviewed in the literature (Table 1).
      Table 1Recurrence rates after AED withdrawal.
      Modified from
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      .
      PopulationsRecurrence ratesYearRef.
      Adults and children

      25 studies, n = 5354
      25% at 1 yr. (95%CI 21–30)

      29% at 2 yrs. (95%CI 24–34)

      range 12–67%
      1994
      • Su L.
      • Di Q.
      • Yu N.
      • Zhang Y.
      Predictors for relapse after antiepileptic drug withdrawal in seizure-free patients with epilepsy.
      Adults and children

      9 studies, n = 1813

      Children only

      19 studies, n = 2758
      45%

      range 23–66%

      30%

      range 12–52%
      2004
      • Specchio J.M.
      • Beghi E.
      Should antiepileptic drugs be withdrawn in seizure free patients?.
      Adults and children

      13 studies, n = 2336
      34% (95%CI 27–43)

      range 12–66%
      2005
      • Berg A.T.
      • Shinnar S.
      Relapse following discontinuation of antiepileptic drugs: a meta-analysis.
      Average recurrence rates (with 95%CI's, when provided) from published meta-analyses or systematic reviews on seizure relapse following AED reduction in medically treated cohorts (references and year of publication given). In most reviews, cohorts that included exclusively adults, both adults and children, or children only, were not analyzed separately.
      The proportion of patients with relapses during or after treatment withdrawal ranges from 12 to 66% (see Table 1). Using life-table analysis, the cumulative probability of remaining seizure-free in children was 66–96% at one year and 61–91% at two years (adults 39–74% and 35–57% respectively). The relapse rate was highest in the first 12 months (especially in the first 6 months) and tended to decrease thereafter. A review of the impact of planned discontinuation of AEDs in seizure-free patients on seizure recurrence yielded 14 observational studies of seizure recurrence after discontinuation and its treatment outcome. Seizure recurrence rates after AED discontinuation ranged between 12 and 66% (mean 34%, 95%CI: 27–43) in the 13 reviewed studies involving over 2300 patients (no data in one study) [
      • Schmidt D.
      • Löscher W.
      Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience.
      ].

      3. Factors influencing risk of relapse

      The factors influencing the overall quite substantial risk of seizure relapse after treatment discontinuation has been well reviewed in the literature Table 2 [
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      ].
      Table 2Clinical predictors of seizure outcome following AED withdrawal.
      Modified from
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      .
      Outcome predictors after AED withdrawalRef.
      Factors related to favorable post-withdrawal outcome

       • Seizure freedom >2 years

       • Control easily achieved on a low dose of one drug

       • No previous unsuccessful attempts at withdrawal

       • Normal neurological exam and EEG

       • Primary generalized epilepsy except JME

       • “Benign” epilepsy syndromes
      • Berg A.T.
      • Shinnar S.
      Relapse following discontinuation of antiepileptic drugs: a meta-analysis.
      ,
      Practice parameter: a guideline for discontinuing antiepileptic drugs in seizure-free patients: summary statement. Report of the Quality Standards. Subcommittee of the American Academy of Neurology.
      Risk factors for relapse after withdrawal in children

       • Older age at onset

       • Remote symptomatic etiology

       • Specific syndromes (e.g. JME particularly after short remission)

       • Family history of seizures

       • History of (atypical) febrile seizures

       • History of neonatal seizures

       • Multiple seizure types

       • Mental retardation

       • Abnormal neuroimaging

       • Polytherapy

       • EEG abnormalities
      • Verrotti A.
      • D’Egidio C.
      • Agostinelli S.
      • Parisi P.
      • Spalice A.
      • Chiarelli F.
      • et al.
      Antiepileptic drug withdrawal in childhood epilepsy: what are the risk factors associated with seizure relapse?.
      ,
      • Shinnar S.
      • Berg A.T.
      • Moshé S.L.
      • Kang H.
      • O’Dell C.
      • Alemany M.
      • et al.
      Discontinuing antiepileptic drugs in children with epilepsy: a prospective study.
      ,
      • Geerts A.T.
      • Niermeijer J.M.
      • Peters A.C.
      • Arts W.F.
      • Brouwer O.F.
      • Stroink H.
      • et al.
      Four-year outcome after early withdrawal of antiepileptic drugs in childhood epilepsy.
      ,
      • Ramos-Lizana J.
      • Aguirre-Rodríguez J.
      • Aguilera-López P.
      • Cassinello-García E.
      Recurrence risk after withdrawal of antiepileptic drugs in children with epilepsy: a prospective study.
      Clinical predictors of seizure relapse, or favorable seizure outcome after AED withdrawal. Listed determinants were extracted from several studies (references given), and apply to epilepsy patients in general or, when specified, to children.
      In a study of 308 children followed up for a year, the recurrence rate was 23.7% in children and most relapses occurred during the first year. An abnormal first EEG and polytherapy were risk factors of recurrence in multivariate analysis. [
      • Incecik F.
      • Herguner O.M.
      • Altunbasak S.
      • Mert G.
      • Kiris N.
      Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy.
      ]. Factors consistently found by Berg and Shinnar [
      • Berg A.T.
      • Shinnar S.
      Relapse following discontinuation of antiepileptic drugs: a meta-analysis.
      ] to indicate a higher-than-average risk of seizure relapse included adolescent-onset epilepsy, partial seizures, presence of an underlying neurological condition, and abnormal EEG findings in children. Adolescent age at onset of seizures had a 1.34 risk of relapse compared to adult age at onset. Remote symptomatic seizures had a 1.55 risk of relapse. An abnormal EEG prior to drug discontinuation was associated with a 1.45 risk of relapse. Factors associated with a lower-than-average risk were childhood epilepsy, idiopathic generalized epilepsy, and – for children – normal EEG. Selected epilepsy syndromes (e.g., benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after treatment withdrawal. AEDs, notably valproic acid, achieve seizure remission in two thirds of patients with juvenile myoclonic epilepsy, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent observations [
      • Senf P.
      • Schmitz B.
      • Holtkamp M.
      • Janz D.
      Prognosis of juvenile myoclonic epilepsy 45 years after onset: seizure outcome and predictors.
      ,
      • Schneider-von Podewils F.
      • Gasse C.
      • Geithner J.
      • Wang Z.I.
      • Bombach P.
      • Berneiser J.
      • et al.
      Clinical predictors of the long-term social outcome and quality of life in juvenile myoclonic epilepsy: 20–65 years of follow-up.
      ] that needs to be assessed in randomized AED withdrawal trials [
      • Koepp M.J.
      • Thomas R.H.
      • Wandschneider B.
      • Berkovic S.F.
      • Schmidt D.
      Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy.
      ].
      The MRC AED Withdrawal Study of adolescents and adults was sufficiently large to develop and test a predictive model for relapse in subgroups of patients continuing or stopping their medication [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Prognostic index for recurrence of seizures after remission of epilepsy.
      ]. The model gives decreasing weight to the following factors: whether or not treatment is withdrawn, period of time seizure-free, taking two or more AEDs, being 16 or older at the time of withdrawal, having myoclonic seizures, and having tonic–clonic seizures of any type. The final factor was an abnormal EEG. Curiously, the model does not include the presence of remote symptomatic epilepsy. However, factors provide surrogate measures for symptomatic epilepsy and capture those aspects of remote symptomatic epilepsy that are most associated with an increased risk. Factors influencing risk of relapse have been summarized [
      • Chadwick D.
      Starting and stopping treatment for seizures and epilepsy.
      ]. As a follow-up the authors developed and tested a prognostic index for the recurrence of seizures after a minimum remission of seizures of two years in people with a history of epilepsy [
      • Medical Research Council Antiepileptic Drug Withdrawal Study Group
      Prognostic index for recurrence of seizures after remission of epilepsy.
      ]. The Cox proportional hazards model identified several factors that increased the risk of seizures recurring. These included being 16 years or older; taking more than one antiepileptic drug; experiencing seizures after starting antiepileptic drug treatment; a history of primary or secondarily generalized tonic–clonic seizures; a history of myoclonic seizures; and having an abnormal electroencephalogram. The risks of seizures recurring decreased with increasing time without seizures. The model allowed estimation of the risk of seizures recurring in the next one and two years under the policies of continued antiepileptic drug treatment and slow withdrawal of drugs. The model seems currently the best available aid for counseling the many patients in the community with epilepsy currently in remission who seek advice about the risks of seizures recurring if they stop antiepileptic drug treatment. The model requires validation in a broad population of patients.

      4. Seizure outcome after relapse

      One important limitation of the randomized benchmark studies we discussed above is that they do not inform about outcome in patients who suffered a relapse. Relapse and its treatment outcome were evaluated in an ultra-long-term population-based study of 148 patients from the onset of their epilepsy to an average follow-up of 37 years [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy.
      ]. During the study, AEDs were completely discontinued by 90 patients; 58 patients remained on medication. Seizure relapse after AED discontinuation was observed in 33 (37%) of 90 patients at an average follow-up of 32 years. Among 8 of the 33 patients who elected to restart AEDs, 2 achieved 5-year terminal remission (5YTR), but only 10–19 years after restarting treatment. The other 6 patients never achieved 5YTR, and 2 of the 6 never entered a 5-year remission period during follow-up. Factors associated with failure to reach 5YTR after treatment of relapse were symptomatic etiology and localization-related epilepsy. This study showed that AED discontinuation after seizure freedom results in relapse in one-third of patients. Reinstitution of a medication that worked for years surprisingly fails to achieve control in one of four patients. These risks need to be considered, although there is no evidence that discontinuation is responsible for the poor prognosis for treatment of seizure recurrence [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy.
      ].

      5. Poor seizure control after relapse

      Although seizure control was regained within approximately one year in half of the cases becoming seizure free, it took some patients as many as 5–12 years [
      • Schmidt D.
      • Löscher W.
      Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience.
      ]. In a systematic review of 13 studies, seizure recurrence rate after AED discontinuation ranged between 12 and 66% (mean 34%, 95%CI: 27–43) [
      • Schmidt D.
      • Löscher W.
      Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience.
      ]. In these cases, reinstitution of AEDs brought to seizure remission in 64–91% (mean of 14 studies, 80%, 95%CI: 75–85%) after a mean follow-up ranging from 1 to 9 years, with no differences between children and adolescents (84%, 95%CI: 75–93) and adults (80%, 95%CI: 74–86). Although seizure control was regained within approximately one year in half of the cases becoming seizure free, some patients regained seizure control in as many as 5–12 years. In addition, in 19% (95%CI: 15–24%), seizure control was incomplete and chronic drug-resistant epilepsy was seen in up to 23% of patients. Factors associated with poor outcome after treating recurrences were symptomatic etiology, partial epilepsy and cognitive deficits. Interestingly, treatment of a recurrence was not confirmed a predictive factor for a better seizure outcome [
      • Matricardi A.
      • Bertamino F.
      • Risso D.
      Discontinuation of anti-epileptic therapy: a retrospective study of 86 children and adolescents.
      ]. In the MRC Antiepileptic Drug Withdrawal trial the risk of recurrence was also similar in patients who relapsed after withdrawal of AEDs and in those who relapsed while remaining on treatment [
      • Chadwick D.
      • Taylor J.
      • Johnson T.
      Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. The MRC Antiepileptic Drug Withdrawal Group.
      ].
      As discussed below, in 19% (mean of 14 studies, 95%CI: 15–24%), resuming medication did not control the epilepsy as before, and chronic drug-resistant epilepsy with many seizures over as many as five years was seen in up to 23% of patients with a recurrence [
      • Schmidt D.
      • Löscher W.
      Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience.
      ]. In a longitudinal long-term study of childhood-onset epilepsy, it took 24 patients 8 years (mean, median 7.0 years, range: 5–20 years) to re-enter long-term remission after the last recurrence and it was more than 10 years in 5 of the 24 patients [
      • Sillanpää M.
      • Schmidt D.
      Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy.
      ]. Delays in re-gaining seizure control, defined as 1-year remission, were already noted in an early observational study from the Netherlands [
      • Overweg J.
      • Binnie C.D.
      • Oosting J.
      • Rowan A.J.
      Clinical and EEG prediction of seizure recurrence following antiepileptic drug withdrawal.
      ]. Among 41 patients, seizure control was regained within 6 months in only 40%. In addition, as will be discussed in detail below, 3 of the 41 patients never became seizure-free again during a follow-up of 5 years and could be considered to be drug-resistant [
      • Overweg J.
      • Binnie C.D.
      • Oosting J.
      • Rowan A.J.
      Clinical and EEG prediction of seizure recurrence following antiepileptic drug withdrawal.
      ].

      6. Seizures despite continued treatment

      In fact, there is no evidence that continued treatment with AEDs guarantees permanent seizure freedom. In a prospective, long-term population-based study of 144 patients followed on average for 37.0 years, 67% were in terminal remission, with or without treatment [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ]. However, 28 patients (19%) achieved terminal remission following a relapse after early or late remission, suggesting a remitting–relapsing pattern, and 20 patients (14%) had a relapse after prolonged remission and did not re-enter remission, indicating a worsening course of the disease.

      7. How to stop AEDs

      Based on the available data, the following general recommendations are briefly summarized here [
      • Beghi E.
      • Giussani G.
      • Grosso S.
      • Iudice A.
      • La Neve A.
      • Pisani F.
      • et al.
      Withdrawal of antiepileptic drugs: guidelines of the Italian League Against Epilepsy.
      ,
      • Schmidt D.
      AED discontinuation may be dangerous for seizure-free patients.
      ]. AED discontinuation requires a careful risk-benefit assessment in view of the undeniable risks involved. These risks include difficulties to predict individual seizure outcome after discontinuation, frequent seizure recurrence, particularly in high-risk patients, and the consequences of seizure recurrence. In addition, successful treatment of seizure recurrence is neither invariably immediate nor assured. Physicians may consider to prudently refrain from encouraging AED discontinuation in high-risk patients [
      • Beghi E.
      • Giussani G.
      • Grosso S.
      • Iudice A.
      • La Neve A.
      • Pisani F.
      • et al.
      Withdrawal of antiepileptic drugs: guidelines of the Italian League Against Epilepsy.
      ,
      • Schmidt D.
      AED discontinuation may be dangerous for seizure-free patients.
      ].
      The difficulty of the decision making how to stop AEDs arises firstly from a lack of understanding of the mechanism(s) through which anti-seizure drug treatment with AEDs may or may not interact with epileptogenesis and patterns of progression or remission which are part of the natural history of epilepsy [
      • Sillanpää M.
      • Schmidt D.
      Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study.
      ]. The traditional concept of using conventional anti-seizure drugs that provide symptomatic seizure relief to prevent the relapse of seizures or epilepsy after stopping AEDs has failed for an important minority of patients up to now. More recently, however, hope is on the horizon with a search for biomarkers and discovery of a new class of agents, called anti-epileptogenic drugs, which were specifically developed for prevention of epilepsy. Are people with a significant period without seizures cured (i.e., their seizure freedom is no longer dependent on treatment) of the condition, or is it simply symptomatic seizure relief in the presence of drug treatment? Ideally, future drug development might provide agents that work both ways. By combining anti-seizure effects with antiepileptogenic effects any seizure relapse and of the underlying epilepsy will be prevented after stopping drug treatment in remission [
      • Löscher W.
      • Klitgaard H.
      • Twyman R.E.
      • Schmidt D.
      New avenues for antiepileptic drug discovery and development.
      ,
      • Schmidt D.
      • Friedman D.
      • Dichter M.A.
      Anti-epileptogenic clinical trial designs in epilepsy: issues and options.
      ]. Secondly, there is little information available to accurately quantify the risk of stopping AEDs for the individual patient. Thirdly, there is concern about unwanted chronic side effects of AEDs. Particular concerns may arise for children with developing brains and women in the child-bearing years where reduction in the risk of fetal malformation and other adverse effects may be particularly harmful. The perceived quality of health of adults with childhood-onset epilepsy was better without drug therapy whether they were in remission or not [
      • Sillanpää M.
      • Haataja L.
      • Shinnar S.
      Perceived impact of childhood-onset epilepsy on quality of life as an adult.
      ].
      Finally, one has to consider that, as a consequence of progression of epilepsy, continuing treatment does not guarantee continued seizure freedom either. Given the many areas of uncertainty it is not surprising that stopping AEDs in patients with prolonged seizure remission is still a matter of debate. Although the probability of remaining seizure-free after treatment discontinuation ranges from 70% at best to 25% at worst, the main challenge is to offer patients an accurate estimate of their individual risk. Identifying patients at greater risk for relapse and for poor remission after relapse may be difficult and even drug resistance may develop unexpectedly in some patients who have been seizure-free on treatment for many years [
      • Schmidt D.
      AED discontinuation may be dangerous for seizure-free patients.
      ]. As a caveat, the decision to withdraw or withhold treatment must be individualized. In any patient, the decision to discontinue treatment should also take into account social aspects like driving license, job and leisure activities as well as emotional and personal factors and adverse effects or drug interactions. Patients will ultimately have to decide themselves whether they wish to discontinue drug treatment.

      8. The pitfalls of stopping epilepsy treatment

      The list of possible pitfalls in stopping AEDs is long (Table 3). The main pitfalls stem from issues in assessing the individual risk-benefit balance and factors influencing seizure relapse including the duration of the seizure-free period, and the length of the tapering period.
      Table 3List of possible pitfalls to consider when counseling patients about stopping AEDs following long-term remission.
      Modified from
      • Braun K.P.
      • Schmidt D.
      Stopping antiepileptic drugs in seizure-free patients.
      .
      Pitfall 1. The patient wants to continue treatment despite the physicians urge to stop AEDs
      Pitfall 2. Under-communicating the risks of stopping AEDs
      Pitfall 3. Failure to appreciate that individual outcome of stopping AEDs is not predictable
      Pitfall 4. Failure to relate the seizure-free period to prior seizure frequency
      Pitfall 5. Overstating the benefits of continued treatment
      Pitfall 6. Overstating the benefits of stopping AEDs
      Pitfall 7. Stopping AEDs is not necessarily the end of treatment
      Pitfall 8. Should physicians encourage seizure-free patients to discontinue AEDs?
      Pitfall 9. Should I withdraw AEDs fast or slow?
      Pitfall 10. Early versus late AED withdrawal?

      9. Conclusions

      Although seizures are not expected to recur in most (70%) individuals but prediction of individual outcome before withdrawal remains uncertain. Patients in whom recurrence occurs have still good chances of achieving renewed seizure freedom, although this may take several years. It is assuring that the occurrence of a recurrence itself does not seem to have important consequences: most patients do not suffer complications from a relapse and 80% eventually become seizure-free again. There is no proof that AED withdrawal itself negatively affects long-term seizure outcomes in patients who became seizure-free under AED treatment AED discontinuation unveils the natural history of the epilepsy in medically treated patients.
      On the other hand, prolonged AED treatment after 2 years without seizures does not guarantee lifelong seizure remission in adults and children. In this light, discontinuation of drug treatment is not dangerous but exposes patients who were seizure-free for years to a transient two-fold risk of seizures for the first 2 years after stopping AEDs. In addition, as shown above, 20% of patients who were seizure-free for years, do not become seizure-free immediately after restarting AED treatment after relapse. Nevertheless, stopping AEDs is a valuable option in most low-risk patients with epilepsy who are seizure-free for two years or longer. The decision to withdraw or withhold treatment in these cases must be, however, individualized. Despite the benefits, in a conservative approach, planned discontinuation of AED in seizure free patients should not be encouraged by physicians, except for patients with benign idiopathic epilepsy of childhood and absence epilepsy of childhood. The decision is primarily driven by assessing the individual risk of relapse after stopping treatment and by patient preference after informed consent. Although moderate, and most likely not causally related to stopping AEDS the risk must be mentioned when discussing AED discontinuation or taper in seizure-free patients. In any patient, beyond school age the individualized decision to discontinue treatment should also take into account social aspects like driving license, job and leisure activities as well as emotional and personal factors and adverse effects or drug interactions, and patients will ultimately have to decide themselves whether they wish to discontinue drug treatment.

      Conflict of interest statement

      I declare that I have no conflict of interest.

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